The Th2 transcription factor c-Maf inhibits IL-12p35 gene expression in activated macrophages by targeting NF-kappaB nuclear translocation. Academic Article uri icon

Overview

abstract

  • The inflammatory response of macrophages to infectious agents is a highly dynamic and orchestrated process involving the release of a variety of inflammatory mediators, including interleukin-12 (IL-12), as a consequence of the recognition of the pathogens. Regulation of IL-12 gene expression by the anti-inflammatory cytokine IL-10 represents a major homeostatic process underlying host-pathogen and host-self interactions. Our group first reported that the Th2-specific transcription factor c-Maf is expressed also in macrophages treated with lipopolysaccharide (LPS) and IL-10. When overexpressed, c-Maf can potently suppress IL-12 production. However, c-Maf does not appear to be a physiologic regulator of IL-12p40 gene transcription because p40 production is not dysregulated in c-Maf-deficient macrophages. In this study, we investigated the role of c-Maf in regulation of the transcription of the p35 gene, which encodes the chain that is rate limiting in the synthesis of the heterodimeric IL-12. We report that c-Maf is a physiologic modulator of IL-12p35 gene expression and IL-12p70 production. We identify a novel NF-kappaB element within the proximal p35 promoter and show that c-Maf inhibits p35 transcription by antagonizing the effects of NF-kappaB, especially c-Rel, on p35 activation. It does so not by directly interacting with the target DNA but by interfering with the nuclear localization of NF-kappaB c-Rel. This study contributes to our understanding of the molecular basis of the homeostatic regulation of IL-12 production by c-Maf, which plays a dual role both in the function of antigen-presenting cells (APCs) and in T helper cell differentiation.

publication date

  • September 1, 2007

Research

keywords

  • Cell Nucleus
  • Interleukin-12 Subunit p35
  • Macrophage Activation
  • Macrophages
  • NF-kappa B
  • Proto-Oncogene Proteins c-maf

Identity

Scopus Document Identifier

  • 34748818985

Digital Object Identifier (DOI)

  • 10.1089/jir.2007.0006

PubMed ID

  • 17892401

Additional Document Info

volume

  • 27

issue

  • 9